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Alcohol use disorder (AUD) is a debilitating disorder, yet currently approved pharmacotherapies to treat AUD are under-utilized. The three medications approved by the US Food and Drug Administration (FDA) for the indication of AUD are disulfiram, acamprosate, and naltrexone. The current landscape of pharmacotherapies for AUD suggests opportunities for improvement. Clinical trials investigating novel pharmacotherapies for AUD traditionally use abstinence-based drinking outcomes or no heavy drinking days as trial endpoints to determine the efficacy of pharmacotherapies. These outcomes are typically measured through patient self-report endorsements of their drinking. Apart from these traditional outcomes, there have been recent developments in novel endpoints for AUD pharmacotherapies. These novel endpoints include utilizing the World Health Organization (WHO) risk drinking level reductions to promote a harm-reduction endpoint rather than an abstinence-based endpoint. Additionally, in contrast to patient self-report measurements, biological markers of alcohol use may serve as objective endpoints in AUD pharmacotherapy trials. Lastly, the National Institute on Alcohol Abuse and Alcoholism (NIAAA) definition of recovery from AUD and patient-oriented outcomes offer new frameworks to consider endpoints associated with more than alcohol consumption itself, such as the provider-patient experiences with novel pharmacotherapies. These recent developments in new endpoints for AUD pharmacotherapies offer promising future opportunities for pharmacotherapy development, so long as validity and reliability measures are demonstrated for the endpoints. A greater breadth of endpoint utilization may better capture the complexity of AUD symptomatology.

Objectives: Alcohol‐related concerns commonly present to the emergency department (ED), with a subset of individuals experiencing the symptoms of an alcohol use disorder (AUD). As such, examining the efficacy of pharmacological anti‐craving treatment for AUD in the ED is of increasing interest. The objective of this systematic review was to evaluate the direct evidence assessing the efficacy of providing anti‐craving medications for AUD treatment in the ED. Methods: A systematic search was conducted according to the patient‐intervention‐control‐outcome question: (P) adults (≥18 years old) presenting to the ED with an AUD (including suspected AUD); (I) anti‐craving medications (i.e., naltrexone, acamprosate, gabapentin); (C) no prescription or placebo; (O) reduction of repeat ED visits, engagement in addiction services, reductions in heavy drinking days, reductions in any drinking and amount consumed (or abstinence), and in relapse. Two reviewers independently assessed articles for inclusion and conducted risk of bias assessments for included studies. Results: From 143 potentially relevant articles, 6 met inclusion criteria: 3 clinical trials, and 3 case studies. The clinical trials identified evaluated oral versus extended‐release naltrexone, monthly extended‐release naltrexone injections, and disulfiram. Both oral and extended‐release naltrexone resulted in decreased alcohol consumption. Monthly extended‐release naltrexone injections resulted in significant improvements in drinking and quality of life. Although out of scope, the disulfiram studies identified did not result in an improvement in drinking in comparison to no medication. Conclusions: Overall, there are few studies directly examining the efficacy of anti‐craving medications for AUD in the ED, although the limited evidence that exists is supportive of naltrexone pharmacotherapy, particularly extended‐release injection formulation. Additional randomized controlled trials are necessary for substantive direct evidence on anti‐craving medication initiation in the ED. [ABSTRACT FROM AUTHOR]

Alcohol use disorder (AUD) is a highly prevalent but severely under-treated disorder, with only three widely-approved pharmacotherapies. Given that AUD is a very heterogeneous disorder, it is unlikely that one single medication will be effective for all individuals with an AUD. As such, there is a need to develop new, more effective, and diverse pharmacological treatment options for AUD with the hopes of increasing utilization and improving care. In this qualitative literature review, we discuss the efficacy, mechanism of action, and tolerability of approved, repurposed, and novel pharmacotherapies for the treatment of AUD with a clinical perspective. Pharmacotherapies discussed include: disulfiram, acamprosate, naltrexone, nalmefene, topiramate, gabapentin, varenicline, baclofen, sodium oxybate, aripiprazole, ondansetron, mifepristone, ibudilast, suvorexant, prazosin, doxazosin, N-acetylcysteine, GET73, ASP8062, ABT-436, PF-5190457, and cannabidiol. Overall, many repurposed and novel agents discussed in this review demonstrate clinical effectiveness and promise for the future of AUD treatment. Importantly, these medications also offer potential improvements towards the advancement of precision medicine and personalized treatment for the heterogeneous AUD population. However, there remains a great need to improve access to treatment, increase the menu of approved pharmacological treatments, and de-stigmatize and increase treatment-seeking for AUD.

Background and aims: Despite the significant burden of alcohol use disorder (AUD) and availability of safe and effective medications for AUD (MAUD), population-level estimates of access and engagement in AUD-related care are limited. The aims of this study were to generate a cascade of care for AUD in British Columbia (BC), Canada, and to estimate the impacts of MAUD on health outcomes. Design: This was a retrospective population-based cohort study using linked administrative health data. Setting: British Columbia, Canada, 2015-2019. Participants: Using a 20% random sample of BC residents, we identified 7231 people with moderate-to-severe alcohol use disorder (PWAUD; overall prevalence = 0.7%). Measurements: We developed a six-stage AUD cascade (from diagnosis to ≥6 months retention in MAUD) among PWAUD. We evaluated trends over time and estimated the impacts of access to MAUD on AUD-related hospitalizations, emergency department visits and death. Findings: Between 2015 and 2019, linkage to AUD-related care decreased (from 80.4% to 46.5%). However, rates of MAUD initiation (11.4% to 24.1%) and retention for ≥1 (7.0% to 18.2%), ≥3 (1.2% to 4.3%) or ≥6 months (0.2% to 1.6%) increased significantly. In adjusted analyses, access to MAUD was associated with reduced odds of experiencing any AUD-related adverse outcomes, with longer retention in MAUD showing a trend to greater odds reduction: adjusted odds ratio (95% CI) ranging from 0.59 (0.48-0.71) for MAUD retention <1 month to 0.37 (0.21-0.67) for ≥6 months retention. Conclusions: Access to medications for alcohol use disorder among people with moderate-to-severe alcohol use disorder in British Colombia, Canada increased between 2015 and 2019; however, initiation and retention remained low. There was a trend between longer retention in medications for alcohol use disorder and greater reductions in the odds of experiencing alcohol use disorder-related adverse outcomes. [ABSTRACT FROM AUTHOR]

Alcohol Use Disorder (AUD) is a chronic disease characterized by excessive drinking, increased craving, development of tolerance and withdrawal symptoms toward alcohol. Anti-craving drugs, psychotherapy, and supportive therapy (vitamin supplements) play a major role in managing AUD and preventing relapse. This study focuses on the prescribing pattern of anti-craving drugs among AUD patients. A prospective observational study was conducted for 6 months in the Department of Psychiatry of a multispeciality hospital in south India with a sample size of 169 AUD patients. Anti-craving drugs of each patient were analyzed. Males were majorly diagnosed with AUD. Approximately equal distribution of newly diagnosed cases and existing cases were seen. Most of the inpatients were treated with anti-craving drugs like benzodiazepines, ondansetron, baclofen, or topiramate, while outpatients were treated with benzodiazepines, ondansetron, or baclofen along with psychotherapy and supportive therapy. Craving was the common factor for relapse. Patients were initially treated with the benzodiazepines in tapering or continued dose, along with ondansetron, baclofen, or topiramate. Psychotherapy and supportive therapy were given to all the patients and most of them were discharged with benzodiazepines, ondansetron, or baclofen. Several factors played a significant role in the starting of alcohol and relapse. [ABSTRACT FROM AUTHOR]

ObjectivePharmacological treatments that can concomitantly address cigarette smoking and heavy drinking stand to improve health care delivery for these highly prevalent co-occurring conditions. This superiority trial compared the combination of varenicline and naltrexone against varenicline alone for smoking cessation and drinking reduction among heavy-drinking smokers.MethodsThis was a phase 2 randomized double-blind clinical trial. Participants (N=165) who were daily smokers and drank heavily received either 2 mg/day of varenicline plus 50 mg/day of naltrexone or 2 mg/day of varenicline plus matched placebo pills for 12 weeks. Primary outcomes were 7-day point prevalence of nicotine abstinence (bioverified by a breath CO reading ≤5 ppm) at the 26-week follow-up and number of drinks per drinking day during the 12-week treatment phase.ResultsSmoking abstinence at week 26 was significantly higher in the varenicline plus placebo condition than in the varenicline plus naltrexone condition (N=37 [45.1%] compared with N=22 [26.5%]). For drinks per drinking day, there was a medication effect favoring the combination of varenicline and naltrexone over varenicline alone across the 12-week treatment phase, although it did not meet the significance threshold.ConclusionsThese findings suggest that smoking cessation and drinking reduction can be concomitantly targeted with pharmacotherapy and that while varenicline alone may be sufficient as a smoking cessation aid in heavy-drinking smokers, the combination of varenicline and naltrexone may confer benefits with regard to drinking outcomes, particularly during the 12-week period of active medication treatment.

In March 2019, a scientific meeting was held at the University of California, Los Angeles (UCLA) Luskin Center to discuss approaches to expedite the translation of neurobiological insights to advances in the treatment of alcohol use disorder (AUD). A guiding theme that emerged was that while translational research in AUD is clearly a challenge, it is also a field ripe with opportunities. Herein, we seek to summarize and disseminate the recommendations for the future of translational AUD research using four sections. First, we briefly review the current landscape of AUD treatment including the available evidence-based treatments and their uptake in clinical settings. Second, we discuss AUD treatment development efforts from a translational science viewpoint. We review current hurdles to treatment development as well as opportunities for mechanism-informed treatment. Third, we consider models of translational science and public health impact. Together, these critical insights serve as the bases for a series of recommendations and future directions. Towards the goal of improving clinical care and population health for AUD, scientists are tasked with bolstering the clinical applicability of their research findings so as to expedite the translation of knowledge into patient care.

BackgroundDirect biomarkers such as phosphatidylethanol (PEth) have the capability to detect heavy alcohol use, but it is unclear how strongly self-reported reduction in alcohol use correlates with reduction in PEth. We sought to explore the strength of correlation between reductions in self-reported alcohol use and change in PEth among a sample of women living with HIV (WLWH) who participated in a clinical trial to reduce heavy alcohol use. We also sought to determine whether this correlation was stronger in women with lower body mass index (BMI) and women without an alcohol use disorder (AUD).Methods81 WLWH (mean age = 48.7, 80% Black) engaging in a randomized trial of naltrexone versus placebo with a positive baseline PEth (≥8 ng/ml), and alcohol use data at baseline, 2, and 7 months were included in this analysis. Spearman correlation coefficients were compared to measure the correlation between baseline PEth and number of drinks per week by demographic, biological, and alcohol use factors. Mini-International Neuropsychiatric Interview was used to screen for AUD. Further analyses were stratified by BMI and AUD. Spearman correlation coefficients were calculated for the change in PEth and the change in number of drinks per week over 7 months, including 3 time-points: baseline, 2, and 7 months.ResultsAt baseline, the correlation between baseline PEth and the number of drinks per week was significantly stronger for those with a BMI ≤25 compared to those with a BMI > 25 (r = 0.66; r = 0.26, respectively). Similarly, the correlation between baseline PEth and number of drinks was stronger for those who did not screen positive for AUD compared with those who did (r = 0.66; r = 0.25, respectively). When stratifying by BMI, a low-to-moderate correlation (r = 0.32, p = 0.02) was present for persons with a BMI > 25; when stratifying by AUD, a moderate correlation (r = 0.50, p

BackgroundHuman laboratory paradigms are a pillar in medication development for alcohol use disorders (AUD). Neuroimaging paradigms, in which individuals are exposed to cues that elicit neural correlates of alcohol craving (e.g., mesocorticolimbic activation), are increasingly utilized to test the effects of AUD medications. Elucidation of the translational effects of these neuroimaging paradigms on human laboratory paradigms, such as self-administration, is warranted. The current study is a secondary analysis examining whether alcohol cue-induced activation in the ventral striatum is predictive of subsequent alcohol self-administration in the laboratory.MethodsNon-treatment-seeking heavy drinkers of East Asian descent (n = 41) completed a randomized, placebo-controlled, double-blind, crossover experiment on the effects of naltrexone on neuroimaging and human laboratory paradigms. Participants completed 5 days of study medication (or placebo); on day 4, they completed a neuroimaging alcohol taste cue-reactivity task. On the following day (day 5), participants completed a 60-minute alcohol self-administration paradigm.ResultsMultilevel Cox regressions indicated a significant effect of taste cue-elicited ventral striatum activation on latency to first drink, Wald χ2  = 2.88, p = 0.05, such that those with higher ventral striatum activation exhibited shorter latencies to consume their first drink. Similarly, ventral striatum activation was positively associated with total number of drinks consumed, F(1, 38) = 5.90, p = 0.02. These effects were significant after controlling for alcohol use severity, OPRM1 genotype, and medication. Other potential regions of interest (anterior cingulate, thalamus) were not predictive of self-administration outcomes.ConclusionsNeuroimaging alcohol taste cue paradigms may be predictive of laboratory paradigms such as self-administration. Elucidation of the relationships among different paradigms will inform how these paradigms may be used synergistically in experimental medicine and medication development.

Naltrexone (NTX) has been widely studied for the treatment of alcohol use disorder with overall support for its efficacy. The mechanisms of action of naltrexone are thought to involve attenuation of the hedonic effects of alcohol and potentiation of its aversive effects. In order to provide a quantitative estimate of the effects of naltrexone on subjective response to alcohol, the aims of this meta-analytic review are to examine the effects of naltrexone across four domains of subjective response. Meta-analyses of naltrexone effects on alcohol craving (k = 16, N = 686), stimulation (k = 15, N = 675), sedation (k = 18, N = 777), and negative mood (k = 9, N = 281) suggested that under laboratory conditions and compared with placebo, naltrexone reduces craving (Hedges g = -0.252; SE = 0.054; 95% CI, -0.375 to -0.130; P

BackgroundAlcohol use disorder (AUD) and its associated consequences remain significant public health concerns. Given that AUD represents a spectrum of severity, treatment options represent a continuum of care, ranging from single-session brief interventions to more intensive, prolonged, and specialized treatment modalities.ObjectiveThis qualitative literature review seeks to describe the best practices for AUD by placing a particular emphasis on identifying those practices which have received the most empirical support.MethodThis review summarizes psychological and pharmacological intervention options for AUD treatment, with a focus on the relapse prevention phase of recovery. Psychological and pharmacological treatments are summarized in terms of the empirical evidence favoring each approach and the level of AUD severity for which they are most indicated.Scientific significanceOne of the broad assertions from this review is that while AUD is highly prevalent, seeking treatment for AUD is not. There are a myriad of behavioral and pharmacological treatments that have shown compelling evidence of efficacy for the treatment of AUD. In the behavioral treatment literature, cognitive behavioral therapy has received the most consistent support. Opioid antagonism (via naltrexone) has been the most widely studied pharmacotherapy and has produced moderate effect sizes. While none of the treatments reviewed herein represents a so-called silver bullet for AUD, they each have the potential to significantly improve the odds of recovery. Precision medicine, or the identification of best treatment matches for individual patients, looms as an important overarching goal for the field, although specific matches are not yet sufficiently reliable in their empirical evidence to warrant clinical dissemination.

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Alcohol consumption is a major risk factor for the acquisition of HIV/AIDS and is associated with greater disease burden and mortality among those who become HIV-infected. Of the extant pharmacological treatments for alcohol use disorders, naltrexone is recognized as one of the most efficacious, producing robust reductions in alcohol craving and use. Given that treatment with oral naltrexone has been limited by problems with adherence, which are particularly prevalent among individuals with multiple chronic, co-occurring conditions, long-acting formulations may be a promising approach for HIV-infected substance users. However, little is known about the barriers to initiation of extended-release naltrexone (XR-NTX) treatment among alcohol users living with HIV. In this report we present and discuss the content analysis of open-ended survey questions, as well as lessons learned, with regards to barriers to initiation and maintenance of XR-NTX treatment collected as part of an RCT evaluating a cognitive behavioral text messaging intervention for HIV-infected adults with alcohol use disorders. Barriers to initiation and maintenance of XR-NTX pharmacotherapy among HIV+ individuals with alcohol use disorders seem to fall in one of two categories: [1] barriers that are amenable to change, which include distance and transportation issues, fear of injections, and belief that alcohol use does not warrant pharmacotherapy, and [2] barriers that are not amenable to change, such as the potential interaction of XR-NTX with another medication regimen.

BackgroundBiomarkers can play a key role in supplementing self-report information in alcohol research. In this study, we examined phosphatidylethanol (PEth) in comparison with self-reported alcohol use over time in a randomized controlled trial.MethodsParticipants were women living with HIV enrolled in a randomized placebo-controlled trial of naltrexone for reducing hazardous drinking. Drinking behavior was measured using Timeline Followback (TLFB), and PEth as a biomarker using dried blood spots. Data collected at baseline, and months 2 and 7 were analyzed. In addition to calculated Spearman's correlations, mixed-effects modeling was used to evaluate the changes in self-reported drinking and PEth, respectively, adjusting for body mass index (BMI).ResultsA total of 194 participants (83% black, mean age 48) were included in the analysis. PEth levels were significantly correlated with self-reported drinking via TLFB, Spearman's r = 0.21 at baseline, r = 0.29 at 2 months, and r = 0.28 at 7 months, respectively. No demographic or health factors, except for BMI, was associated with whether self-report was consistent with PEth. Mixed-effects model indicated that self-reported drinking showed significantly greater reductions in the naltrexone treatment group than the placebo group at the 2- and 7-month visits, whereas PEth measure only showed this difference at the 7-month follow-up.ConclusionsThe magnitude of the correlation between PEth and self-reported alcohol consumption was small. Caution is needed when using either self-report or PEth as a sole outcome measure for alcohol behavior changes in clinical trials.

Development of effective treatments for alcohol use disorder (AUD) represents an important public health goal. This review provides a summary of completed preclinical and clinical studies testing pharmacotherapies for the treatment of AUD. We discuss opportunities for improving the translation from preclinical findings to clinical trial outcomes, focusing on the validity and predictive value of animal and human laboratory models of AUD. Specifically, while preclinical studies of medications development have offered important insights into the neurobiology of the disorder and alcohol's molecular targets, limitations include the lack of standardized methods and streamlined processes whereby animal studies can readily inform human studies. Behavioral pharmacology studies provide a less expensive and valuable opportunity to assess the feasibility of a pharmacotherapy prior to initiating larger scale clinical trials by providing insights into the mechanism of the drug, which can then inform recruitment, analyses, and assessments. Summary tables are provided to illustrate the wide range of preclinical, human laboratory, and clinical studies of medications development for alcoholism. Taken together, this review highlights the challenges associated with animal paradigms, human laboratory studies, and clinical trials with the overarching goal of advancing treatment development and highlighting opportunities to bridge the gap between preclinical and clinical research.

Aim There are potential clinical, ethical and legal concerns with overdosing benzodiazepines (or barbiturates) for the treatment of moderate to severe alcohol withdrawal symptoms (AWS) through telemedicine or ambulatory outpatients. A rapid systematic review to (a) qualitatively summarize the non-benzodiazepine treatment alternatives, (b) evaluate the quality of evidence for the same to effectively manage moderate to severe AWS. Methods We conducted searches on PubMed (January 1990 to 31 March 2020), Cochrane Central Register of Controlled Trials, and Google Scholar. We selected the English language randomized controlled trials (RCTs) assessing the efficacy and adverse effects of non-benzodiazepine and non-barbiturate medications among adults with a diagnosis of AWS. Data extraction was done in a predefined format. Risk of bias (RoB) assessment and qualitative synthesis of evidence was done with the RoB2 tool and Grading of Recommendations Assessment, Development, and Evaluation (GRADE) proGDT. Results Thirty-four RCTs were included. Gabapentin (n  = 6), carbamazepine (n  = 5), baclofen (n  = 5), valproate (n  = 3), clonidine/lofexidine (n  = 3) and acamprosate (n  = 2) had more than one trial with a particular comparison group. Four studies were found to have a low ROB. The GRADE evidence summary showed gabapentin had a 'moderate' level of evidence against standard benzodiazepine treatments for reducing the severity of AWS. The level of certainty was 'low' for carbamazepine, baclofen and valproate and 'very low' for acamprosate and clonidine/lofexidine. Reported adverse events between these alternative medications and benzodiazepines or placebo were generally unremarkable. Conclusions Although benzodiazepines remain the treatment of choice for AWS, during particular circumstances, gabapentin could be an alternative although like benzodiazepines is not without risk when used in the community. Future RCTs must aim to improve upon the quality of evidence. [ABSTRACT FROM AUTHOR]

Background and aim: Pharmacotherapy for alcohol use disorder (AUD) is recommendable, but under‐used, possibly due to deficient knowledge of medications. This study aimed to investigate the real‐world effectiveness of approved pharmacological treatments (disulfiram, acamprosate, naltrexone and nalmefene) of AUD. Design A nation‐wide, register‐based cohort study. Setting: Sweden. Participants: All residents aged 16–64 years living in Sweden with registered first‐time treatment contact due to AUD from July 2006 to December 2016 (n = 125 556, 62.5% men) were identified from nation‐wide registers. Measurements The main outcome was hospitalization due to AUD. The secondary outcomes were hospitalization due to any cause, alcohol‐related somatic causes, as well as work disability (sickness absence or disability pension), and death. Mortality was analysed with between‐individual analysis using a traditional multivariate‐adjusted Cox hazards regression model. Recurrent outcomes, such as hospitalization‐based events and work disability, were analysed with within‐individual analyses to eliminate selection bias. Findings Naltrexone combined with acamprosate [hazard ratio (HR) = 0.74; 95% confidence interval (CI) = 0.61–0.89], combined with disulfiram (HR = 0.76, 95% CI = 0.60–0.96) and as monotherapy (HR = 0.89, 95% CI = 0.81–0.97) was associated with a significantly lower risk of AUD‐hospitalization compared with no use of AUD medication. Similar results were found for risk of hospitalization due to any cause. Benzodiazepine use and acamprosate monotherapy were associated with an increased risk of AUD‐hospitalization (HR = 1.18, 95% CI = 1.14–1.22 and HR = 1.10, 95% CI = 1.04–1.17, respectively). No statistically significant effects were found for work disability or mortality. Conclusions: Naltrexone as monotherapy and when combined with disulfiram and acamprosate appears to be associated with lower risk of hospitalization due to any and alcohol‐related causes, compared with no use of alcohol use disorder (AUD) medication. Acamprosate monotherapy and benzodiazepine use appear to be associated with increased risk of AUD‐associated hospitalization. [ABSTRACT FROM AUTHOR]

BackgroundThe goal of the current study was to use tree-based methods (Zhang and Singer, 2010, Recursive Partitioning and Applications, 2nd ed. Springer, New York) to identify predictors of abstinence from heavy drinking in COMBINE (Anton et al. JAMA 2006; 295:2003), the largest study of pharmacotherapy for alcoholism in the United States to date, and to validate these results in PREDICT (Mann et al. Addict Biol 2012; 18:937), a parallel study conducted in Germany.MethodsWe compared a classification tree constructed according to purely statistical criteria to a tree constructed according to a combination of statistical criteria and clinical considerations for prediction of no heavy drinking during treatment in COMBINE. We considered over 100 baseline predictors. The tree approach was compared to logistic regression. The trees and a deterministic forest identified the most important predictors of no heavy drinking for direct testing in PREDICT.ResultsThe tree built using both clinical and statistical considerations consisted of 4 splits based on consecutive days of abstinence (CDA) prior to randomization, age, family history of alcoholism, and confidence to resist drinking in response to withdrawal and urges. The tree based on statistical considerations with 4 splits also split on CDA and age but also on gamma-glutamyl transferase level and drinking goal. Deterministic forest identified CDA, age, and drinking goal as the most important predictors. Backward elimination logistic regression among the top 18 predictors identified in the deterministic forest analyses identified only age and CDA as significant main effects. Longer CDA and goal of complete abstinence were associated with better outcomes in both data sets.ConclusionsThe most reliable predictors of abstinence from heavy drinking were CDA and drinking goal. Trees provide binary decision rules and straightforward graphical representations for identification of subgroups based on response and may be easier to implement in clinical settings.

Background and objectivesAlcohol abuse complicates treatment of HIV disease and is linked to poor outcomes. Alcohol pharmacotherapies, including disulfiram (DIS), are infrequently utilized in co-occurring HIV and alcohol use disorders possibly related to concerns about drug interactions between antiretroviral (ARV) medications and DIS.MethodThis pharmacokinetics study (n=40) examined the effect of DIS on efavirenz (EFV), ritonavir (RTV), or atazanavir (ATV) and the effect of these ARV medications on DIS metabolism and aldehyde dehydrogenase (ALDH) activity which mediates the DIS-alcohol reaction.ResultsEFV administration was associated with decreased S-Methyl-N-N-diethylthiocarbamate (DIS carbamate), a metabolite of DIS (p=.001) and a precursor to the metabolite responsible for ALDH inhibition, S-methyl-N,N-diethylthiolcarbamate sulfoxide (DETC-MeSO). EFV was associated with increased DIS inhibition of ALDH activity relative to DIS alone administration possibly as a result of EFV-associated induction of CYP 3A4 which metabolizes the carbamate to DETC-MeSO (which inhibits ALDH). Conversely, ATV co-administration reduced the effect of DIS on ALDH activity possibly as a result of ATV inhibition of CYP 3A4. DIS administration had no significant effect on any ARV studied.Discussion/conclusionsATV may render DIS ineffective in treatment of alcoholism.Future directionsDIS is infrequently utilized in HIV-infected individuals due to concerns about adverse interactions and side effects. Findings from this study indicate that, with ongoing clinical monitoring, DIS should be reconsidered given its potential efficacy for alcohol and potentially, cocaine use disorders, that may occur in this population.

Compulsive drinking despite serious adverse medical, social and economic consequences is a characteristic of alcohol use disorders in humans. Although frontal cortical areas have been implicated in alcohol use disorders, little is known about the molecular mechanisms and pathways that sustain aversion-resistant intake. Here, we show that nucleus accumbens core (NAcore) NMDA-type glutamate receptors and medial prefrontal (mPFC) and insula glutamatergic inputs to the NAcore are necessary for aversion-resistant alcohol consumption in rats. Aversion-resistant intake was associated with a new type of NMDA receptor adaptation, in which hyperpolarization-active NMDA receptors were present at mPFC and insula but not amygdalar inputs in the NAcore. Accordingly, inhibition of Grin2c NMDA receptor subunits in the NAcore reduced aversion-resistant alcohol intake. None of these manipulations altered intake when alcohol was not paired with an aversive consequence. Our results identify a mechanism by which hyperpolarization-active NMDA receptors under mPFC- and insula-to-NAcore inputs sustain aversion-resistant alcohol intake.

The prevalence of alcohol use disorders (AUDs) has steadily increased in the United States over the last 30 years. Alcohol acts on multiple receptor systems including the nicotinic acetylcholine receptors (nAChRs), which are known to mediate alcohol consumption and reward. We previously reported that the preclinical drug sazetidine-A, a nAChR agonist and desensitizer, reduces alcohol consumption without affecting nicotine consumption in C57BL/6J mice. Here, we found that sazetidine-A enhances the expression of alcohol aversion without affecting the expression or acquisition of conditioned alcohol reward in C57BL/6J mice. Microinjection of sazetidine-A into the ventral midbrain targeting the ventral tegmental area (VTA) reduced binge alcohol consumption, implicating this region in mediating the effects of sazetidine-A. Furthermore, the sazetidine-A-induced reduction in alcohol consumption was mediated by non-α4 containing nAChRs, as sazetidine-A reduced binge alcohol consumption in both α4 knock-out and wild-type mice. Finally, we found that in mice pretreated with sazetidine-A, alcohol induced Fos transcript in Th-, but not Gad2-expressing neurons in the VTA as measured by increased Fos transcript expression. In summary, we find that sazetidine-A enhances the expression of alcohol aversion, which may underlie the reduction in alcohol consumption induced by sazetidine-A. Elucidating the identity of non-α4 nAChRs in alcohol aversion mechanisms will provide a better understanding the complex role of nAChRs in alcohol addiction and potentially reveal novel drug targets to treat AUDs. [ABSTRACT FROM AUTHOR]

It is known as ametistic drugs those that are used in order to correct the dependence of the drug in the case of alcoholism. Amethyst (from Lat. Amethystus, from Gr. Améthystos, without drunkenness), is a transparent quartz, stained violet by the oxides of calcium, sodium, magnesium, iron and manganese, and by hydrocarbons, which is valued as semiprecious stone; heating removes the color of the amethyst or changes it to the yellow of the citrine. The main source places are: Brazil, Uruguay, Ontario and North Carolina. The medications used in the treatment of alcoholism are of three types: aversive (antidipsotropic, interdicting, sensitizing); those that act on the desire to drink (anti-cravings), and those that decrease excessive consumption. This paper reviews about these medications. [ABSTRACT FROM AUTHOR]

Alcohol misuse is often a chronic problem such that relapses following treatment are common. One potential protective factor for alcohol misuse is self-compassion, which includes self-kindness, feelings of common humanity, and mindfulness when faced with personal suffering and hardships. This study tested the hypothesis that self-compassion, and specifically self-compassion promoting facets including self-kindness, common humanity, and mindfulness, were longitudinally associated with reduced alcohol use among a sample of men and women in substance use disorder treatment (N = 62). Results partially supported the hypothesis, in that only the mindfulness facet of self-compassion was associated with decreased alcohol use over time. Sex and age differences as they related to the positive facets of self-compassion and alcohol use emerged. These findings suggest that positive facets of self-compassion may be beneficial factors to cultivate in alcohol treatment programs. [ABSTRACT FROM AUTHOR]

A systematic review and meta‐analysis of approved and off‐label medication treatments for alcohol use disorder has concluded that oral naltrexone and acamprosate have the strongest evidence for reducing alcohol consumption. Trials that directly compared naltrexone and acamprosate did not establish superiority of one of the medications. [ABSTRACT FROM AUTHOR]

Objective: U.S. Food and Drug Administration (FDA)-approved medications exist for the treatment of alcohol use disorders. However, their effectiveness depends on proper adherence to the prescribed regimen. Differences in adherence across medications may have implications for clinical outcomes and may provide helpful information in considering treatment options. This study aims to identify significant differences in adherence if present.Method: A retrospective chart review was conducted in the Veterans Integrated Service Networks (VISN)-7 region of Veterans Affairs hospital and community-based outpatient clinics within South Carolina and Georgia. Prescriptions of FDA-approved alcohol use disorder medications from 2010 through 2015 were reviewed. Adherence was determined by the proportion of days the veteran had oral or injectable medication available over a 6-month period as noted by medication fills (reported as 0%-100% medication availability). We compared adherence for specific medications using chi-square, t test, logistic regression for dichotomous outcomes, and linear regression for continuous outcomes.Results: A total of 715 subjects and 807 medication trials were included. Mean adherence (percentage of days that medication was available) was 41.3% for disulfiram, 44.7% for acamprosate, 49.8% for oral naltrexone, and 54.6% for extended-release injectable naltrexone. The mean adherence was significantly different between disulfiram and oral naltrexone (p = .002) as well as disulfiram and extended-release injectable naltrexone (p = .004). Adherence of 80% was achieved in 11.9%, 19.4%, 22.7%, and 24.4% of treatment courses with disulfiram, acamprosate, naltrexone, and extended-release injectable naltrexone, respectively. These differences were significant for disulfiram versus oral naltrexone (p = .004) and disulfiram versus extended-release injectable naltrexone (p = .05).Conclusions: These results demonstrate that overall adherence to medication-assisted treatment for alcohol use disorder is low across all medications. When directly compared, disulfiram had significantly lower adherence than both oral and extended-release injectable naltrexone. [ABSTRACT FROM AUTHOR]

Alcohol use disorders (AUDs) are a health problem of high prevalence in most communities and such problems account for 5% of the total burden of disease worldwide. Clinical toxicologists are commonly required to treat patients having AUDs and associated drug/alcohol-related harm. There have been recent changes to some of the diagnostic criteria (notably in DSM V) relevant to AUDs, with older terms “alcohol abuse” and “alcohol dependence” no longer being classified. AUDs may sometimes not be clearly recognizable and use of evidence-based screening interventions can help identify such conditions and lead to effective brief interventions (e.g. SBIRT programs in emergency departments). AUDs are viewed as chronic disorders of alcohol consumption occurring across a spectrum of severity. While most AUDs are mild to moderate in severity and usually self-limiting conditions, more severe presentations are more commonly encountered by physicians in emergency settings. Hence, clinical toxicologists are more likely to see patients within the more severe form of disorder, at end of the spectrum of AUDs. Among this group of patients, multi-morbidity and particularly high mortality risk exists, and thus they usually require management collaboration with specialist services. Patients with AUDs are most likely to be recognized by a clinical toxicologist in the following scenarios: following acute heavy alcohol ingestion and subsequently developing acute alcohol intoxication (ethanol toxidrome), following accidental or intentional drug overdosage where alcohol has also been consumed, following acute alcohol consumption that has been associated with behavioral risk-taking and/or self-harming (e.g. poisoning, envenomation, etc.), when alcohol withdrawal reactions are severe requiring hospitalization and possibly following an adverse drug reaction.

Background Although pharmacotherapies are available for alcohol (EtOH) or tobacco use disorders individually, it may be possible to develop a single pharmacotherapy to treat heavy drinking tobacco smokers by capitalizing on the commonalities in their mechanisms of action. Methods Female alcohol-preferring (P) rats were trained for EtOH drinking and nicotine self-administration in two phases: (1) EtOH alone (0 vs. 15% EtOH, 2-bottle choice) and (2) concomitant access, during which EtOH access continued with access to nicotine (0.03 mg/kg/infusion, i.v.) using a 2-lever choice procedure (active vs. inactive lever) in which the fixed ratio (FR) requirement was gradually increased to FR30. When stable co-use was obtained, rats were pretreated with varying doses of naltrexone, varenicline, or r-bPiDI, an α6β2* subtype-selective nicotinic acetylcholine receptor antagonist shown previously to reduce nicotine self-administration. Results While EtOH intake was initially suppressed in phase 2 (co-use), pharmacologically relevant intake for both substances was achieved by raising the "price" of nicotine to FR30. In phase 2, naltrexone decreased EtOH and water consumption but not nicotine intake; in contrast, naltrexone in phase 1 (EtOH only) did not significantly alter EtOH intake. Varenicline and r-bPiDI in phase 2 both decreased nicotine self-administration and inactive lever pressing, but neither altered EtOH or water consumption. Conclusions These results indicate that increasing the "price" of nicotine increases EtOH intake during co-use. Additionally, the efficacy of naltrexone, varenicline, and r-bPiDI was specific to either EtOH or nicotine, with no efficacy for co-use. Nevertheless, future studies on combining these treatments may reveal synergistic efficacy. [ABSTRACT FROM AUTHOR]

Background: Understanding study characteristics' influence on treatment efficacy could improve methodologies and interpretation of findings. We examine study characteristics as predictors of outcomes in clinical trials of medications for alcohol problems.Methods: We obtained data on 23 trials of naltrexone and 22 trials of acamprosate from Cochrane reviews. We extracted data for 14 study characteristics and 3 dependent variables (odds ratio; percent abstinent in placebo; medication conditions). We used general linear models to determine which study characteristics explained the variability among outcomes after controlling for medication characteristics.Results: Study characteristics accounted for 45% of the variance in odds ratio when trials of different medications were combined, 19% among acamprosate, and 48% among naltrexone trials above and beyond medication characteristics. When medications were combined, greater odds ratios were predicted by having more dropouts in the placebo than medication conditions, an earlier publication year, and not receiving industry funding. Whether this was due to effects on placebo or medication conditions was unclear. Among acamprosate trials, smaller sample sizes predicted greater odds ratios, which appeared to be due to more abstinence in medication conditions. Among naltrexone trials, greater odds ratios were predicted by having more dropouts in the placebo than medication conditions and a greater probability of randomizing participants to treatment. This appeared to be due to less abstinence in placebo conditions.Conclusion: Study characteristics influence the assessment of treatment efficacy beyond medication characteristics in alcohol treatment trials. Future studies are needed to determine which study characteristics reliably influence efficacy to help investigators design and help clinicians interpret trials. [ABSTRACT FROM AUTHOR]

Importance: Alcohol consumption is associated with 88 000 US deaths annually. Although routine screening for heavy alcohol use can identify patients with alcohol use disorder (AUD) and has been recommended, only 1 in 6 US adults report ever having been asked by a health professional about their drinking behavior. Alcohol use disorder, a problematic pattern of alcohol use accompanied by clinically significant impairment or distress, is present in up to 14% of US adults during a 1-year period, although only about 8% of affected individuals are treated in an alcohol treatment facility.Observations: Four medications are approved by the US Food and Drug Administration to treat AUD: disulfiram, naltrexone (oral and long-acting injectable formulations), and acamprosate. However, patients with AUD most commonly receive counseling. Medications are prescribed to less than 9% of patients who are likely to benefit from them, given evidence that they exert clinically meaningful effects and their inclusion in clinical practice guidelines as first-line treatments for moderate to severe AUD. Naltrexone, which can be given once daily, reduces the likelihood of a return to any drinking by 5% and binge-drinking risk by 10%. Randomized clinical trials also show that some medications approved for other indications, including seizure disorder (eg, topiramate), are efficacious in treating AUD. Currently, there is not sufficient evidence to support the use of pharmacogenetics to personalize AUD treatments.Conclusions and Relevance: Alcohol consumption is associated with a high rate of morbidity and mortality, and heavy alcohol use is the major risk factor for AUD. Simple, valid screening methods can be used to identify patients with heavy alcohol use, who can then be evaluated for the presence of an AUD. Patients receiving a diagnosis of the disorder should be given brief counseling and prescribed a first-line medication (eg, naltrexone) or referred for a more intensive psychosocial intervention. [ABSTRACT FROM AUTHOR]

Objective: Adults with serious mental illness and comorbid alcohol dependence are at high risk for both high utilization of crisis-driven health care services and criminal justice involvement. Evidence-based medication-assisted treatment (MAT) for alcohol dependence may reduce both crisis service utilization and criminal recidivism. The authors estimated the effect of MAT on behavioral health treatment utilization and criminal justice outcomes for this population.Method: Relevant administrative data were merged from several public agencies in Connecticut for 5,743 adults ≥18 years old who had schizophrenia spectrum disorder, bipolar disorder, or major depressive disorder comorbid with moderate to severe alcohol dependence and who were incarcerated for at least one night during the study window (2002-2009). Longitudinal multivariable regression models were used to estimate the effect of MAT compared with other outpatient substance abuse treatments on inpatient mental health and substance abuse hospitalizations, emergency department visits, criminal convictions, and incarcerations.Results: MAT was associated with significant improvements in clinical outcomes in the 12 months following initiation compared with non-MAT comparison treatment, including greater reductions in mental health hospitalization and emergency department visits and greater improvements in psychotropic medication adherence. No benefits of MAT were found for most criminal justice outcomes, except for significant reductions in felony convictions among adults with bipolar disorder.Conclusions: MAT is underused for treating alcohol dependence, especially among adults with serious mental illness. These results suggest that MAT can have important benefits for clinical outcomes in this population. More research is needed to improve its use in this patient population as well as to address barriers to its availability. [ABSTRACT FROM AUTHOR]

Rationale: Acamprosate (calcium-bis N-acetylhomotaurinate) is the leading medication approved for the maintenance of abstinence, shown to reduce craving and relapse in animal models and human alcoholics. Acamprosate can improve executive functions that are impaired by chronic intermittent ethanol (CIE) exposure. Recent work has suggested that acamprosate’s effects on relapse prevention are due to its calcium component, which raises the question whether its pro-cognitive effects are similarly mediated by calcium.Objectives: This study examined the effects of acamprosate on alcohol-induced behavioral deficits and compared them with the effects of the sodium salt version of N-acetylhomotaurinate or calcium chloride, respectively.Methods: We exposed mice to alcohol via three cycles of CIE and measured changes in alcohol consumption in a limited-access paradigm. We then compared the effects of acamprosate and calcium chloride (applied subchronically for 3 days during withdrawal) in a battery of cognitive tasks that have been shown to be affected by chronic alcohol exposure.Results: CIE-treated animals showed deficits in attentional set-shifting and deficits in novel object recognition. Alcohol-treated animals showed no impairments in social novelty detection and interaction, or delayed spontaneous alternation. Both acamprosate and calcium chloride ameliorated alcohol-induced cognitive deficits to comparable extents. In contrast, the sodium salt version of N-acetylhomotaurinate did not reverse the cognitive deficits.Conclusions: These results add evidence to the notion that acamprosate produces its anti-relapse effects through its calcium moiety. Our results also suggest that improved regulation of drug intake by acamprosate after withdrawal might at least in part be related to improved cognitive function. [ABSTRACT FROM AUTHOR]

Extended-release naltrexone (XRNTX) is an effective treatment for alcohol use disorder (AUD). We sought to evaluate the feasibility, acceptability, and preliminary effectiveness and cost-effectiveness of XRNTX delivered as a stand-alone service to persons with severe AUD who are high utilizers of multiple urgent and emergency medical services (HUMS). Of 15 HUMS persons with severe AUD selected based on chart review, 11 agreed to participate. Participants received a mean of 4.5 injections (range 2-7). Modest benefits from XRNTX were observed in terms of patients' Urge-to-Drink Score and the costs of emergency medical services utilized. Though limited by a small sample size, costs including client utilization and study related expenses during the post-enrollment period were less than client utilization costs in the pre-enrollment period. We also observed non-significant improvements in the number of drinking days, but no change in quality of life as measured by the EQ-5D. Eighty-eight percent of participants perceived XRNTX as helping with their drinking. Findings need to be replicated in a larger study, however if replicated, the cost savings could be substantial. [ABSTRACT FROM AUTHOR]

Changes in cravings to drink alcohol and alcohol use behaviors were examined among 337 patients who were administered extended-release naltrexone (XR-NTX) in conjunction with psychosocial treatment in community-based substance use disorder treatment programs. Cravings and use behaviors were assessed at multiple time points (baseline; weeks 1, 2, and 3 after the first dose; monthly after the first four assessments; and at 30- and 60-days after the last dose). A total of 863 doses (M=2.6, SD=1.8) were administered and the majority of patients (65%) took more than one dose. Alcohol craving scores decreased from 19 to 5.7 after the first dose of XR-NTX. Days of primary alcohol use at admission (M=10.5, SD=10.1) were reduced at discharge (M=to 1.2, SD=4.6). At the first follow-up, 79.8% reported no alcohol use and 77.8% reported no alcohol use at the second follow-up. The expected side effects were reported but the medication was well tolerated and there was no relationship between side effects and subsequent dose. Unexamined or unaccounted for variables (e.g., motivation, external pressures to remain in treatment) are "real world" consequences that may have impacted the outcome of this study. Results indicated that use of the antagonist medication XR-NTX may be related to significant decreases in alcohol craving and use while a patient is in treatment, as well as at 30- and 60-days after the final dose. [ABSTRACT FROM AUTHOR]

Background: Previous reviews have examined the use of theoretically supported combinations of drugs for the treatment of alcohol use disorder. This review seeks to examine the strengths and limitations of current clinical evidence for the use of combined pharmacological interventions intended to treat alcohol use disorder.Objectives: The objective of this review was to identify combinations of pharmacological treatments for alcohol use disorder, and assess the strength of clinical evidence for these treatments.Methods: We conducted searches using PubMed, EMBASE® through Ovid® (1974 to present), MEDLINE® through Ovid® (1946 to present), and Psychinfo® through Ovid® (1806 to present). Our primary search included the terms "alcoholism" and "drug therapy, combination". Search results were restricted to human subjects and English language. Search criteria were not restricted based on study design or patient age. Studies were evaluated for randomization, blinding, group similarity, power determination, outcome reporting, and number of patients analyzed.Results: Nine hundred and eighty-four publications were initially screened for inclusion after duplicates were removed. The search identified 16 publications evaluating drug combinations for the treatment of alcohol use disorder. The majority of published trials included naltrexone combined with one of the following: gabapentin, ondansetron, acamprosate, gamma-hydroxybutyrate, sertraline, quetiapine, or escitalopram plus gamma-hydroxybutyrate. Other combinations included 5-hydroxytryptophan with carbidopa/levodopa, gamma-hydroxybutyrate with disulfiram, acamprosate with disulfiram, and mirtazapine with quetiapine. Interpretation of results across studies was limited by low statistical power, and heterogeneity of drug combinations and outcome measures. Drug combination effect sizes were comparable to those observed in single-agent trials.Conclusions: No significant benefit for the use of combinations over single agents was observed. However, benefit may be observed when combined pharmacological interventions address specific symptoms of alcohol use disorder known to be influenced by combination components, or when combinations are used in specific subpopulations in which combination components demonstrate benefit. [ABSTRACT FROM AUTHOR]